Genetics of Fragile X Syndrome

The genetics of fragile X syndrome

This syndrome was originally called "fragile X" because chromosomes from affected individuals, when viewed in cells cultured
in folate-deficient media, demonstrated a weak point in the long-arm of the X chromosome (Xq27.3), called a "fragile site."

Almost all cases of fragile X syndrome (FXS) are due to an expansion of an unstable CGG repeat sequence that is located in the 5' untranslated region of the FMR-1 gene. Other neurological diseases associated with nucleotide repeat expansions include myotonic dystrophy and Huntington
disease.

The FMR-1 gene codes for the FMR-1 protein (FMRP). Though the function of this protein is unknown, it is a
mRNA binding protein and is implicated in the regulation of synaptic plasticity. [Penagarikano: 2007]

Increasing numbers of repeats in the FMR1 gene are
associated with an increasingly characteristic phenotypic appearance of the disease. However, occasionally there are exceptions
– e.g., males with the full mutation who have no mental retardation and males with mental retardation who do not have the
other characteristics of the syndrome.

In individuals with typical characteristics of FXS, a full mutation expansion usually leads to methylation of the FMR-1 gene.
However, occasionally, individuals with a full mutation will not have methylation of the gene and may not demonstrate typical
characteristics of affected individuals.

There are four allelic
forms of the FMR-1 gene, determined by the number of repeats:

Normal: though not well defined, the maximum number is probably less than 41.

The intermediate form has 41-55 repeats. Individuals with this form do not have relatives with fragile X syndrome nor do they have known unstable
transmission to full mutation forms.

The premutation form has approximately 55 to 199 repeats. Individuals with pre-mutation alleles are at risk for unstable expansion, possibly leading
to transmission of a greater number of repeats to their children. The larger the number of repeats within this range, the
more likely an expansion to the full mutation will occur. The premutation repeat size is more likely to expand when transmitted
by a woman to her children, called maternal anticipation.

The full mutation form has 200 or more repeats. At this point, the gene becomes hypermethylated, no mRNA is produced, and consequently no FMR1 protein (FMRP) is produced – having 400 repeats is not any different clinically than having 210 repeats.

Genetic counseling

Genetic counseling is complicated because FXS does not follow classic Mendelian inheritance. Parents of a child with FXS are
not only at risk of having another child with FXS, but may themselves be affected to some degree.

In general, 33-50% of women who carry the full mutation have significant problems determined by several factors, including
X chromosome inactivation.

Premutation alleles are associated with premature ovarian failure in women and a late-onset neurodegenerative disorder with tremor and ataxia (FXTAS) that occurs in men more often than in women.

Risks for subsequent pregnancies depend on the number of repeats in the mother, demonstrating an X-linked inheritance pattern.
Both male and female offspring of mothers with the full mutation have a 50% risk of inheriting the mutation. For males carrying
the fragile X gene expansion, all daughters will inherit the mutation and no sons will. Prenatal testing is available and
genetic counseling is recommended for all families where pre-mutations or full mutations are identified.

In mothers with premutation alleles, risks for subsequent pregnancies depend on the number of repeats in the pre-mutation.
The risk that offspring will have a full mutation increases with the size of the mother's premutation, called maternal anticipation.
For example, if a mother is a premutation carrier with 80-89 repeats, there is a 60% chance of expanding to a full mutation
in a subsequent pregnancy. This risk increases to a 95% if the maternal pre-mutation has 130-139 repeats. Note that prenatal
testing and diagnosis is available, as well as pre-implantation genetic diagnosis for some families with affected family members.

Testing

The American College of Medical Genetics recommends fragile X testing in children, both males and females, with mental retardation without another etiology, "especially in the presence of a positive family history, a consistent
physical and behavioral phenotype and absence of major structural abnormalities." [ACMG: 1994] See also Genetic testing algorithm for FXS (GeneReviews).

Testing for fragile X is done by polymerase chain reaction and Southern blot analysis. Note that individuals previously tested
by cytogenetic analysis may have falsely negative results, since this testing is not as accurate as the current molecular
genetic testing.

Resources

Information & Support

For Professionals

Genetics in Primary Care Institute (AAP)The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes
health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services
Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Authors

Page Bibliography

ACMG.Fragile X syndrome: diagnostic and carrier testing. Working Group of the Genetic Screening Subcommittee of the Clinical Practice
Committee. American College of Medical Genetics.Am J Med Genet.
1994;53(4):380-1.
PubMed abstract